Implementing Direct Access to Low-Dose Computed Tomography in General Practice—Method,Adaption and Outcome

Background

Early detection of lung cancer is crucial as the prognosis depends on the disease stage. Chest radiographs has been the principal diagnostic tool for general practitioners (GPs), but implies a potential risk of false negative results, while computed tomography (CT) has a higher sensitivity. The aim of this study was to describe the implementation of direct access to low-dose CT (LDCT) from general practice.

Methods

We conducted a cohort study nested in a randomised study. A total of 119 general practices with 266 GPs were randomised into two groups. Intervention GPs were offered direct access to chest LDCT combined with a Continuing Medical Education (CME) meeting on lung cancer diagnosis.

Results

During a 19-month period, 648 patients were referred to LDCT (0.18/1000 adults on GP list/month). Half of the patients needed further diagnostic work-up, and 15 (2.3%, 95% CI: 1.3–3.8%) of the patients had lung cancer; 60% (95% CI: 32.3–83.7%) in a localised stage. The GP referral rate was 61% higher for CME participants compared to non-participants.

Conclusion

Of all patients referred to LDCT, 2.3% were diagnosed with lung cancer with a favourable stage distribution. Half of the referred patients needed additional diagnostic work-up. There was an association between participation in CME and use of CT scan. The proportion of cancers diagnosed through the usual fast-track evaluation was 2.2 times higher in the group of CME-participating GPs. The question remains if primary care case-finding with LDCT is a better option for patients having signs and symptoms indicating lung cancer than a screening program. Whether open access to LDCT may provide earlier diagnosis of lung cancer is yet unknown and a randomised trial is required to assess any effect on outcome.

Trial Registration

Clinicaltrials.gov NCT01527214     

Hipposin,a histone-derived antimicrobial peptide in Atlantic halibut (Hippoglossus hippoglossus L.)

A novel 51-residue antimicrobial peptide (AMP) from the skin mucus of Atlantic halibut (Hippoglossus hippoglossus L.) was isolated using acid extraction, and cationic exchange and reversed phase chromatography. The complete amino acid sequence of the AMP, termed hipposin, was determined by automated Edman degradation and mass spectrometry to be SGRGKTGGKARAKAKTRSSRAGLQFPVGRVHRLLRKGNYAHRVGAGAPVYL. The N-terminal amino group was acetylated. The theoretical mass of hipposin was calculated to be 5458.4 Da, which was in good agreement with the mass of 5459 Da determined by matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). Hipposin was shown to be derived from histone H2A by PCR amplifying the encoding sequences from Atlantic halibut genomic DNA. The peptide showed sequence similarity with the 39-mer AMP buforin I of Asian toad and the 19-mer AMP parasin I of catfish. Fifty of the fifty-one residues in hipposin were identical to the N-terminal region of histone H2A from rainbow trout. Hipposin showed strong antimicrobial activity against several Gram-positive and Gram-negative bacteria and activity could be detected down to hipposin concentrations of 0.3 microM (1.6 microg/ml). Hipposin without N-terminal acetylation was prepared by solid-phase peptide synthesis and shown to have the same antimicrobial activity as the natural acetylated peptide. Thus, hipposin is a new broad-spectrum histone-derived AMP found in the skin mucus of Atlantic halibut.     

Role of adipocyte lipid-binding protein (ALBP) and acyl-CoA binding protein (ACBP) in PPAR-mediated transactivation

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are activated by a number of fatty acids and fatty acid derivatives. By contrast, we have recently shown that acyl-CoA esters display PPAR antagonistic properties in vitro. We have also shown that the adipocyte lipid binding protein (ALBP), the keratinocyte lipid binding protein (KLBP) and the acyl-CoA binding protein (ACBP) exhibit a prominent nuclear localization in differentiating 3T3-L1 adipocytes. Similarly, ectopic expression of these proteins in CV-1 cells resulted in a primarily nuclear localization. We therefore speculated that FABPs and ACBP might regulate the availability of PPAR agonists and antagonists by affecting not only their esterification in the cytoplasm but also their transport to and availability in the nucleus. We show here that coexpression of ALBP or ACBP exerts a negative effect on ligand-dependent PPAR transactivation, when tetradecylthioacetic (TTA) is used as ligand but not when the thiazolidinedione BRL49653 is used as ligand. The results presented here do not support the hypothesis that ALBP facilitates the transport of the fatty acid-type ligands to the nucleus, rather ALBP appears to sequester or increase the turn-over of the agonist. Similarly, our results are in keeping with a model in which ACBP increase the metabolism of these ligands.     

Vascular Disease and Risk Stratification for Ischemic Stroke and All-Cause Death in Heart Failure Patients without Diagnosed Atrial Fibrillation: A Nationwide Cohort Study

Background

Stroke and mortality risk among heart failure patients previously diagnosed with different manifestations of vascular disease is poorly described. We conducted an observational study to evaluate the stroke and mortality risk among heart failure patients without diagnosed atrial fibrillation and with peripheral artery disease (PAD) or prior myocardial infarction (MI).

Methods

Population-based cohort study of patients diagnosed with incident heart failure during 2000–2012 and without atrial fibrillation, identified by record linkage between nationwide registries in Denmark. Hazard rate ratios of ischemic stroke and all-cause death after 1 year of follow-up were used to compare patients with either: a PAD diagnosis; a prior MI diagnosis; or no vascular disease.

Results

39,357 heart failure patients were included. When compared to heart failure patients with no vascular disease, PAD was associated with a higher 1-year rate of ischemic stroke (adjusted hazard rate ratio [HR]: 1.34, 95% confidence interval [CI]: 1.08–1.65) and all-cause death (adjusted HR: 1.47, 95% CI: 1.35–1.59), whereas prior MI was not (adjusted HR: 1.00, 95% CI: 0.86–1.15 and 0.94, 95% CI: 0.89–1.00, for ischemic stroke and all-cause death, respectively). When comparing patients with PAD to patients with prior MI, PAD was associated with a higher rate of both outcomes.

Conclusions

Among incident heart failure patients without diagnosed atrial fibrillation, a previous diagnosis of PAD was associated with a significantly higher rate of the ischemic stroke and all-cause death compared to patients with no vascular disease or prior MI. Prevention strategies may be particularly relevant among HF patients with PAD.     

Comparative analysis of cobalamin binding kinetics and ligand protection for intrinsic factor, transcobalamin, and haptocorrin.

Changes in the absorbance spectrum of aquo-cobalamin (Cbl x OH(2)) revealed that its binding to transcobalamin (TC) is followed by slow conformational reorganization of the protein-ligand complex (Fedosov, S. N., Fedosova, N. U., Nex?, E., and Petersen, T. E. (2000) J. Biol. Chem. 275, 11791-11798). Two phases were also observed for TC when interacting with a Cbl-analogue cobinamide (Cbi), but not with other cobalamins. The slow phase had no relation to the ligand recognition, since both Cbl and Cbi bound rapidly and in one step to intrinsic factor (IF) and haptocorrin (HC), namely the proteins with different Cbl specificity. Spectral transformations observed for TC in the slow phase were similar to those upon histidine complexation with Cbl x OH(2) and Cbi. In contrast to a closed structure of TC x Cbl x OH(2), the analogous IF and HC complexes revealed accessibility of Cbl's upper face to the external reagents. The binders decreased sensitivity of adenosyl-Cbl (Cbl x Ado) to light in the range: free ligand, IF x, HC x, TC x Cbl x Ado. The spectrum of TC x Cbl small middle dotAdo differed from those of IF and HC and mimicked Cbl x Ado participating in catalysis. The above data suggest presence of a histidine-containing cap shielding the Cbl-binding site in TC. The cap coordinates to certain corrinoids and, possibly, produces an incapsulated Ado-radical when Cbl small middle dotAdo is bound.     

Urstylidae – a new family of abyssal isopods (Crustacea: Asellota) and its phylogenetic implications

We report three new species of isopod crustaceans that belong to a rare higher taxon of asellote Isopoda. This taxon does not fit into current classifications. The isopods occurred in abyssal soft sediments, near manganese nodules, and in the vicinity of hydrothermal vents. Given their wide spatial occurrence across the Atlantic and Pacific Oceans, a cosmopolitan distribution is assumed. A cladistic analysis revealed a close relationship with the Macrostylidae, a common representative of the deep‐sea macrofauna. Analyses of character evolution across the Janiroidea showed sufficient synapomorphies to justify the erection of U rstylis gen. nov. and the new family Urstylidae based on the three new species. All taxa are described in this paper. Urstylidae is characterized, amongst other apomorphies, by an elongate habitus with spade‐like head; uropods are long, styliform; one pleonite is free; antennal merus and carpus are relatively short; the first pereopod is carpo‐propodosubchelate, and more robust and shorter than pereopod II. Several characters, such as the pereopods’ posterior scale‐like claw that basally encloses the distal sensilla may be interpreted as ancestral when compared to the situation in the highly derived Macrostylidae. © 2014 The Linnean Society of London     

Land‐atmosphere exchange of methane from soil thawing to soil freezing in a high‐Arctic wet tundra ecosystem

The land‐atmosphere exchange of methane (CH₄) and carbon dioxide (CO₂) in a high‐Arctic wet tundra ecosystem (Rylekærene) in Zackenberg, north‐eastern Greenland, was studied over the full growing season and until early winter in 2008 and from before snow melt until early winter in 2009. The eddy covariance technique was used to estimate CO₂ fluxes and a combination of the gradient and eddy covariance methods was used to estimate CH₄ fluxes. Small CH₄ bursts were observed during spring thawing 2009, but these existed during short periods and would not have any significant effect on the annual budget. Growing season CH₄ fluxes were well correlated with soil temperature, gross primary production, and active layer thickness. The CH₄ fluxes remained low during the entire autumn, and until early winter. No increase in CH₄ fluxes were seen as the soil started to freeze. However, in autumn 2008 there were two CH₄ burst events that were highly correlated with atmospheric turbulence. They were likely associated with the release of stored CH₄ from soil and vegetation cavities. Over the measurement period, 7.6 and 6.5 g C m^?2 was emitted as CH₄ in 2008 and in 2009, respectively. Rylekærene acted as a C source during the warmer and wetter measurement period 2008, whereas it was a C sink for the colder and drier period of 2009. Wet tundra ecosystems, such as Rylekærene may thus play a more significant role for the climate in the future, as temperature and precipitation are predicted to increase in the high‐Arctic.     

Consequences of inferring diet from feeding guilds when estimating and interpreting consumer–resource stoichiometry

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Estimation of separable direct and indirect effects in continuous time

Many research questions involve time-to-event outcomes that can be prevented from occurring due to competing events. In these settings, we must be careful about the causal interpretation of classical statistical estimands. In particular, estimands on the hazard scale, such as ratios of cause-specific or subdistribution hazards, are fundamentally hard to interpret causally. Estimands on the risk scale, such as contrasts of cumulative incidence functions, do have a clear causal interpretation, but they only capture the total effect of the treatment on the event of interest; that is, effects both through and outside of the competing event. To disentangle causal treatment effects on the event of interest and competing events, the separable direct and indirect effects were recently introduced. Here we provide new results on the estimation of direct and indirect separable effects in continuous time. In particular, we derive the nonparametric influence function in continuous time and use it to construct an estimator that has certain robustness properties. We also propose a simple estimator based on semiparametric models for the two cause-specific hazard functions. We describe the asymptotic properties of these estimators and present results from simulation studies, suggesting that the estimators behave satisfactorily in finite samples. Finally, we reanalyze the prostate cancer trial from Stensrud et al. (2020).     

Sub-fossils of cladocerans in the surface sediment of 135 lakes as proxies for community structure of zooplankton,fish abundance and lake temperature

To elucidate the possibilities of using zooplankton remains in the surface sediment to describe present-days community structure and population dynamics of zooplankton, fish abundance and temperature, we compared contemporary data sampled in the pelagial during summer with the sediment record from the upper 1 cm of the sediment in 135 lakes covering a latitude gradient from Greenland in the north to New Zealand in the south. The abundance of three genera Bosmina, Daphnia and Ceriodaphnia of the total pool of ephippia was significantly related to the total abundance of the same taxa in the pelagic zone. However, in most lakes the abundance of Ceriodaphnia was higher in the sediment than in the water, which may be attributed to the overall preference by this genus for the littoral habitat. Using contemporary data from 27 Danish lakes sampled fortnightly during summer for 10 years, we found substantial inter-annual variations in the abundance of Daphnia spp., Ceriodaphnia spp., B. longirostris and B. coregoni. Yet, the sediment record mimicked the medium level well for most of the lakes, which suggests that the sediment record provides an integrated picture of the pelagic cladoceran community, which otherwise can be obtained only by long-term frequent contemporary sampling for several years. The contribution of Daphnia to the sum of Daphnia and Bosmina ephippia was negatively correlated with the abundance of fish expressed as catch per night in multi-mesh sized gill nets (CPUE). Yet, region-specific differences occurred, which partly could be eliminated by including nutrient state expressed as total phosphorus (TP) in a multiple regression. The average ratio of ephippia to the sum of ephippia and carapaces of Bosmina varied 40-fold between the sampling regions and was significantly negatively related to summer mean air temperature, and for Danish lakes also, albeit weakly, to fish CPUE but not to chlorophyll a. Apparently, temperature is the most important factor determining the ratio of parthenogenetic to ephippia producing specimens of Bosmina. We conclude that the sediment record of cladocerans is a useful indicator of community structure of pelagic cladocerans and the abundance of fish and temperature.